Malignant melanoma is the most lethal form of skin cancer with an increasing incidence in the United States. Unfortunately, no curative treatment exists for metastatic melanoma. Despite the significant advance of molecularly targeted approaches in treating metastatic melanoma over the past years, the long-term survival remains <10%. Thus, there is an urgent need to develop new treatment strategies for metastatic melanoma. Melanocortin-1 receptor (MC1R) is a distinct molecular target due to its over-expression on >80% of human metastatic melanomas. We have developed a novel class of MC1R-targeting lactam-cyclized CycMSHhex peptides for melanoma imaging. The remarkable first-in-man clinical results regarding the visualization of melanoma metastases using our CycMSHhex peptide clearly demonstrate the clinical significance of MC1R in melanoma imaging, as well as underscore the urgent need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma. Thus, we propose to develop novel MC1R-targeting theranostic (diagnostic & therapeutic) ?Pb/Pb-DOTA-Linker-Nle-CycMSHhex peptides for imaging-guided therapy of melanoma in this project. We hypothesize that DOTA-Linker-Nle-CycMSHhex peptides can specifically bind to MC1Rs and target matched-pair theranostic ?Pb/Pb to human melanoma cells for imaging-guided therapy. We will use hydrocarbon and polyethylene glycol (PEG) linkers to improve melanoma uptake and clearance properties of ?Pb/Pb-DOTA-Linker-Nle-CycMSHhex, and then examine the therapeutic efficacies of selected Pb-DOTA-Linker-Nle-CycMSHhex peptides in human melanoma xenografts and metastases in this project. We have been awarded 4 US patents for our novel CycMSHhex peptides, demonstrating the originality and novelty of this project. The objective of this project is to develop novel MC1R-targeting theranostic ?Pb/Pb-DOTA-Linker-Nle- CycMSHhex peptides to treat metastatic melanoma via imaging-guided therapy. Our positive preliminary results strongly support our hypothesis and research design. Importantly, we have assembled a strong research team with established expertise that is uniquely suited to carry out this exciting translational project. The success of this project will provide a novel imaging tool (?Pb-peptide) to identify MC1R-positive patients who will benefit from Pb-peptide treatments, to determine safe and efficacious doses, and to monitor patients' responses to treatments. Moreover, the success of this project will open the avenue of treating metastatic melanoma with the combination of receptor-targeted alpha therapy (Pb-peptide) and other treatments in the future, providing patients with personalized diagnoses and treatments. Identification of novel theranostic peptides in this project will pave the way for evaluating this novel class of peptide radiopharmaceuticals in US FDA-approved clinical trials in the future, and enhance the opportunities of cures to patients with metastatic melanoma.